1-231694237-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018662.3(DISC1):c.479G>T(p.Trp160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,230 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (3 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.665

Genes affected

DISC1 (HGNC:2888): (DISC1 scaffold protein) This gene encodes a protein with multiple coiled coil motifs which is located in the nucleus, cytoplasm and mitochondria. The protein is involved in neurite outgrowth and cortical development through its interaction with other proteins. This gene is disrupted in a t(1;11)(q42.1;q14.3) translocation which segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

TSNAX-DISC1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034786463).
• BP6: Variant 1-231694237-G-T is Benign according to our data. Variant chr1-231694237-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 714799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.479G>T	p.Trp160Leu	missense_variant	2/13	ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.1200G>T		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.479G>T	p.Trp160Leu	missense_variant	2/13	5	NM_018662.3	A2

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00631

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00143 AC: 355 AN: 248772 Hom.: 2 AF XY: 0.00138 AC XY: 186 AN XY: 134708

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00123 AC: 1793 AN: 1461850 Hom.: 3 Cov.: 32 AF XY: 0.00122 AC XY: 886 AN XY: 727228

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00553

Gnomad4 NFE exome AF: 0.00130

Gnomad4 OTH exome AF: 0.000828

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.00150 AC XY: 112 AN XY: 74518

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00631

Gnomad4 NFE AF: 0.00178

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.000714

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00172 AC: 209

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

DISC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	3.0
Dann	Benign	0.74
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.81	T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L;L;.;L;L;L;L;.;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.1	N;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.026
Sift	Benign	0.44	T;T;.;.;T;T;.;T;T;.;.;T;.
Sift4G	Benign	0.55	T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.10	B;.;.;.;B;B;.;.;B;.;.;B;.
Vest4		0.18
MVP		0.22
MPC		0.20
ClinPred		0.0088	T
GERP RS		-0.65
Varity_R		0.047
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143796295; hg19: chr1-231829983;